Dyskinesia is an abnormal movement involuntarily appearing on the four limbs and face. Representative symptoms thereof include tongue rolling, neck torsion, hip rocking as well as bending and stretching of arms and legs. Once dyskinesia appears, normal motor functions are impaired and thus a patient is forced to have a restricted life.
It has been known that dyskinesia is induced mainly as a side effect of long term administration of a drug such as a therapeutic agent for schizophrenia or Parkinson's disease. For instance, long term use of the therapeutic agent for schizophrenia induces particularly dyskinesia of the mouth and/or tongue and a therapeutic agent for Parkinson's disease, L-DOPA, also causes dyskinesia, both of which are well-known cases. Because the abnormal dyskinesia movements occur at any place and a patient who has a fear of being seen such symptoms by others avoids going out of the house, so that the quality of life of the patient is decreased, which is also problematic.
Known methods for treating or preventing dyskinesia include a method wherein the onset of dyskinesia is prevented by reducing L-DOPA dose as much as possible in a treatment for Parkinson's disease; a method wherein the therapy is carried out with a selective dopamine D2 receptor antagonist such as tiapride, an NMDA receptor antagonist such as amantadine, or a muscle relaxant such as a botulinus toxin; and a method wherein the onset of dyskinesia is prevented by avoiding a long term irresponsibly administration of a large amount of a therapeutic agent for schizophrenia. There are not however effective therapeutic or prophylactic methods and thus urgent development of a treating agent or prophylactic agent is desired.
Meanwhile, it has been recently reported that an opioid κ receptor agonist, U50488 (trans-(±)-(3,4-dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidin-1-yl)-cyclohexyl]acetamide) suppresses L-DOPA-induced dyskinesia while deteriorates Parkinson's symptoms (Non-patent Literature 1: Cox H et al., Exp Neural. 2007, Volume 205, Issue 1, p.101-107). Patent Literature 1 describes that β-funaltrexamine (β-FNA), albeit an opioid μ antagonist, which is a compound having a morphinan skeleton and close to the effective component used in the present application in terms of a chemical structure, suppresses dyskinesia (Patent Literature 1: WO00/003715). Meanwhile, the compound used as effective component in the present application is described with its analgesic action, diuresis action and opioid κ agonist activity in Patent Literature 2. In addition, its antiussive action and its use as brain cell protective agent, antipruritic drug, therapeutic agent for hyponatremia, ORL-1 receptor antagonist, therapeutic agent for neuropathic pain, antipruritic drug for tunica conjunctiva, therapeutic agent for neuropsychiatric disorder, therapeutic agent for septicemia and antipruritic drug for multiple sclerosis are described in patent literatures (Patent Literatures 3 to 12: WO 95/001178, WO 95/003307, WO 98/023290, WO 99/005146, Japanese Laid-open Patent Application (Kokai) No. 2000-53572, WO 01/014383, Japanese Laid-open Patent Application (Kokai) No. 2001-163784, WO 02/078744, WO 02/089845, and WO 06/095836). In particular, the patent literature disclosing the use of the compound as a brain cell protective agent also describes its effect on Parkinson's disease but does not disclose its effectiveness against dyskinesia at all.
Dyskinesia occurs as a side effect of a drug therapy for Parkinson's disease, schizophrenia or the like, and is generally aggravated by continuous administration of a therapeutic agent. On the other hand, as described in Non-patent Literature 1 (Cox H et al., Exp Neurol., 2007, Volume 205, Issue 1, p. 101-107), a drug having a therapeutic effect on dyskinesia is thought to cause aggravation of the primary disease. Thus a fact that a drug effective on the primary disease has a therapeutic effect on dyskinesia can be said to be against a common technical knowledge.
Non-patent Literature 1: Cox H et al, Exp Neurol. 2007, Volume 205, Issue 1, p. 101-107
Patent Literature 1: WO 00/003715
Patent Literature 2: WO 93/015081
Patent Literature 3: WO 95/001178
Patent Literature 4: WO 95/003307
Patent Literature 5: WO 98/023290
Patent Literature 6: WO 99/005146
Patent Literature 7: Japanese Laid-open Patent Application (Kokai) No. 2000-53572
Patent Literature 8: WO 01/014383
Patent Literature 9: Japanese Laid-open Patent Application (Kokai) No. 2001-163784
Patent Literature 10: WO 02/078744
Patent Literature 11: WO 02/089845
Patent Literature 12: WO 06/095836